WILL (When to Induce Labour to Limit risk in pregnancy hypertension) - a multicentre, randomised controlled trial

TITLE: WILL (When to Induce Labour to Limit risk in pregnancy hypertension) – a multicentre, randomised controlled trial OBJECTIVES: WILL aims to address timing of delivery for women with chronic or gestational hypertension that develops by 37+6 weeks. The research question is whether planned early term delivery at 38+0 to 38+3 weeks (compared with expectant care until at least 40+0 weeks) will reduce a composite of ‘poor maternal outcome’ (co-primary, severe systolic hypertension and/or one or more maternal morbidities) without increasing neonatal care unit admission for =4hr (co-primary) measured to hospital discharge. A secondary objective is to examine whether the intervention will decrease Caesarean sections (important secondary outcome), stillbirth, and cost. DESIGN: Pragmatic, randomised, multicentre trial (with an internal pilot) PARTICIPANT POPULATION AND SAMPLE SIZE: The trial will take place in consultant-led maternity units in the UK, and randomise 540 women/group. INCLUSION: • maternal age >=16 years; • chronic or gestational hypertension; • singleton pregnancy; • live fetus; • gestational age of 36+0 to 37+6 weeks; • documented informed consent to participate. Hypertension is defined as an elevated BP (systolic BP >=140mmHg or diastolic BP >=90mmHg, twice at least 4hr apart) or receipt of medication to lower BP. Chronic hypertension is defined as hypertension diagnosed before pregnancy or before 20 weeks’ gestation. Gestational hypertension is defined as hypertension diagnosed at >=20 weeks’ gestation, without evidence of new proteinuria. EXCLUSION: • contraindication to either one of trial arms; • BP >=160mmHg systolic or >=110mmHg diastolic until BP is controlled; • major fetal anomaly; • participation in another timing of delivery trial. A major fetal anomaly is one that is anticipated to result in admission to a neonatal care unit after birth. Women with co-morbidities (eg, renal diseases) will be included if there is inadequate relevant timing of delivery evidence and clinicians are in equipoise. INTERVENTIONS: At the 36+0 to 37+6 week routine antenatal visit, women will be assessed for eligibility and consented, and then if still undelivered at 37+0-6 weeks, they will be randomised (by 1:1 allocation, minimised by centre, hypertension type, and prior Caesarean) to: • Planned delivery at 38+0 to 38+3 weeks by labour induction (local protocol) or elective Caesarean (if previously indicated or by women’s choice); or • Expectant care until at least 40+0 weeks, changed to usual care from 11 Aug 2022, with maternal and fetal monitoring (local protocol), awaiting spontaneous labour or delivery indicated by clinical need (e.g., refractory severe hypertension or pre-eclampsia). OUTCOME MEASURES: PRIMARY (MOTHER): Composite of poor maternal outcome until primary hospital discharge home or 6 weeks after delivery (whichever is earlier). All components should decrease with planned early term delivery: •Systolic BP >=160mmHg which the national MBRRACE-UK reports (of Confidential Enquiry into Maternal Deaths and Morbidity) states is a clinical emergency requiring urgent treatment; and/or • Maternal death or morbidity, adapted from Delphi consensus in hypertensive pregnancy: stroke; eclampsia; blindness; uncontrolled hypertension; inotropic support; pulmonary oedema; respiratory failure; myocardial ischaemia or infarction; hepatic dysfunction, hepatic haematoma or rupture; acute kidney injury; transfusion. This outcome was adapted from fullPIERS and iHOPE Delphi consensus, and is being used in the HTA-funded PHOENIX trial (ISRCTN01879376), to reflect the multisystem nature of pregnancy hypertension complications that are not always mediated through pre-eclampsia. PRIMARY (BABY): Neonatal care unit admission for >=4hr. Although neonatal morbidity at term is mainly mild and usually not life or health-threatening, admission to a neonatal unit is distressing to women (at minimum, due to the separation from the infant) and expensive for the health system. SECONDARY: • Caesarean delivery and indications (maternal, fetal, both- all specified); • instrumental vaginal delivery and indications (maternal, fetal, both- all specified); • individual components of poor maternal outcome (listed above under primary outcome); • composite of poor maternal outcome (as for maternal primary outcome with the addition of wound infection) informed by follow-up to 6 weeks postpartum; • indications for special neonatal care (baby) (respiratory problems, low Apgar score, birthweight [low or high], sepsis work-up, hyper- or hypo-glycaemia, other); • neonatal care unit admission for =4hr informed by follow-up to 28 days postpartum; • stillbirth • neonatal death • haemorrhage (ante- or post-partum) • breastfeeding established and exclusive breastfeeding (both measured at hospital discharge) • maternal satisfaction (measured at hospital discharge); and • cost-consequence analysis from NHS perspective (enrolment to hospital discharge). Although not a focus of this study, consistent with HTA guidance, women will be asked for consent to link delivery with routinely collected clinical and school census data to enable future study. SAMPLE SIZE: 540 randomised/group based on reduction in poor maternal outcome (25% to 17%; 90% power; 5% alpha, superiority) that will give 90% power to detect a non-inferiority margin of difference in incidence of neonatal care unit admission >=4 hrs of 9% from 23% (2.5% alpha, non-inferiority) and a decrease in Caesarean (45% to 35%, 90% power, 5% alpha, superiority) - similar to changes in HYPITAT I. An independent Data Monitoring Committee will review safety and outcome data at least annually. PLANNED CARE PATHWAYS will specify timing of delivery. Otherwise, all women will receive an integrated package of care based on current NICE care pathways (eg, antihypertensives). TIMETABLE: Based on 30% uptake and site start-up, we will recruit for 4 years in 85 centres (5000 deliveries/year average), plus 6 months for each of study start-up and data cleaning, write-up, and results presentation. A 9-month internal pilot (20 sites) assessed study processes and recruitment.